The present invention relates generally to microfluidic systems, devices, and methods. More particularly, the present invention provides structures and methods that are useful for handling and sequentially introducing large numbers of samples into devices having microfluidic channels.
Considerable work is now underway to develop microfluidic systems, particularly for performing chemical, clinical, and environmental analysis of chemical and biological specimens. The term microfluidic refers to a system or device having a network of chambers connected by channels, in which the channels have microscale dimensions, e.g., having at least one cross sectional dimension in the range from about 0.1 μm to about 500 μm. Microfluidic substrates are often fabricated using photolithography, wet chemical etching, injection molding, embossing, and other techniques similar to those employed in the semiconductor industry. The resulting devices can be used to perform a variety of sophisticated chemical and biological analytical techniques.
Microfluidic analytical systems have a number of advantages over conventional chemical or physical laboratory techniques. For example, microfluidic systems are particularly well adapted for analyzing small samples sizes, typically making use of samples on the order of nanoliters and even picoliters. The channel defining substrates may be produced at relatively low cost, and the channels can be arranged to perform numerous specific analytical operations, including mixing, dispensing, valving, reactions, detections, electrophoresis, and the like. The analytical capabilities of microfluidic systems are generally enhanced by increasing the number and complexity of network channels, reaction chambers, and the like.
Substantial advances have recently been made in the general areas of flow control and physical interactions between the samples and the supporting analytical structures. Flow control management may make use of a variety of mechanisms, including the patterned application of voltage, current, or electrical power to the substrate (for example, to induce and/or control electrokinetic flow or electrophoretic separations). Alternatively, fluid flows may be induced mechanically through the application of differential pressure, acoustic energy, or the like. Selective heating, cooling, exposure to light or other radiation, or other inputs may be provided at selected locations distributed about the substrate to promote the desired chemical and/or biological interactions. Similarly, measurements of light or other emissions, electrical/electrochemical signals, and pH may be taken from the substrate to provide analytical results. As work has progressed in each of these areas, the channel size has gradually decreased while the channel network has increased in complexity, significantly enhancing the overall capabilities of microfluidic systems.
One particularly advantageous application for microfluidic techniques is to screen collections of large numbers of samples. There has long been a need to rapidly assay numerous compounds for their effects on various biological processes. For example, enzymologists have long sought improved substrates, inhibitors, and/or catalysts for enzymatic reactions. The pharmaceutical industry has focussed on identifying compounds that may block, reduce, or enhance the interactions between biological molecules, such as the interaction between a receptor and its ligand. The ability to rapidly process numerous samples for detection of biological molecules relevant to diagnostic or forensic analysis could also have substantial benefits for diagnostic medicine, archaeology, anthropology, and modern criminal investigations. Modern drug discovery has long suffered under the limited throughput of known assay systems for screening collections of chemically synthesized molecules and/or natural products. Unfortunately, the dramatic increase in the number of test compounds provided by modern combinatorial chemistry and human genome research has overwhelmed the ability of existing techniques for assaying sample compounds.
The throughput capabilities of existing sample handling and assaying techniques have been improved using parallel screening methods in a variety of robotic sample handling and detection system approaches. While these improvements have increased the number of compounds which can be tested by a system, these existing systems generally require a significant amount of space to accommodate the samples and robotic equipment, and the sample handling equipment often has extremely high costs. Additionally, large quantities of reagents and compounds are used in performing the assays, which reagents have their own associated costs, as well as producing significant waste disposal problems. Use of small amounts of test compounds with these existing techniques can increase the errors associated with fluid handling and management due to evaporation, dispensing errors, and surface tension effects.
A high throughput screening assay system using microfluidic devices has previously been described. Published P.C.T. Patent Application No. WO 98/00231, the full disclosure of which is hereby incorporated by reference for all purposes, describes a microlaboratory system which can sequentially introduce a large number of test compounds (typically contained in multi-well plates) into a number of assay chips or microfluidic devices. This advantageous system allows testing of a large number of sample compounds with a compact sample handling arrangement, while the manipulation of picoliter or nanoliter volumes of chemicals can both enhance the speed of each chemical analysis and minimize sample and waste product volumes. Hence, such a microlaboratory system represents a significant advancement for handling and testing large numbers of chemical and biological compounds.
Although the proposed application of microfluidic devices to high throughput screening provides a tremendous increase in the number of sample compounds which can be cost effectively tested, still further improvements would be desirable. In particular, it would be helpful to develop devices and methods which were adapted to efficiently handle the tremendous number of sample compounds that might be tested with such a system. It would be best if these sample handling techniques were flexibly adaptable to the wide variety of analyses that might be performed in a microfluidic screening system. Such sample handling systems should be tailored to take advantage of the strengths of a microfluidic analytical device, while minimizing any limitations of microfluidic analysis, and while accommodating any particular sensitivity of these new structures which might otherwise induce error. Ideally, all of these enhanced capabilities will be provided in a compact, high throughput system which can be produced at a moderate cost.